Surgical and chemical (LH-RH agonists) castration are widely used for the treatment of patients with prostate cancer. Apart from impotence, the most frequent long-term side effect of such therapy is the onset of distressing hot flashes (also known as hot flushes) similar to those seen in postmenopausal women. Vasomotor hot flashes and sweats occur in up to 80% of prostate cancer patients following either orchiectomy or treatment with LH-RH agonists. As many as one-third of these patients will experience persistent and frequent symptoms severe enough to cause significant discomfort and inconvenience. In one study in prostate cancer patients undergoing surgical castration, Charig and Rundle, (Urology (1989) 18: 175-178), found that 76% of their patients experienced hot flashes, and 30% believed their symptoms warranted treatment. In this study hot flashes started on average two to three months post-operatively and lasted in some patients for more than three years. However, the pattern in any individual patient was unpredictable. These results are in agreement with those of another study conducted in Sweden, as an attempt to quantify the degree of flashing by measuring skin blood flow and water evaporation. Froedin, T., The Prostate (1985) 7:203-208. The results of several other clinical trials reveal an incidence of hot flashes and sweats in about 40-80% of surgically or chemically castrated prostate cancer patients. One-third of all patients seek palliation and in many patients the symptoms may start as early as one to two weeks after castration.
Hot flashes can be extremely bothersome. They sometimes occur several times an hour, and they often occur at night. Hot flashes and outbreaks of sweats occurring during the night can cause sleep deprivation. Symptoms observed such as nervousness, fatigue, depression or inability to concentrate are considered to be caused by the sleep deprivation following night sweats. (Kramer, P., et al., In: Murphy G., et al., 3rd Int'l Symposium on Recent Advances in Urological Cancer Diagnosis and Treatment--Proceedings. Paris, France: SCI: 3-7 (1992)). Hot flashes can start without any warning. The attacks can last up to thirty minutes and vary in their frequency from several times a week to more than a dozen attacks per day. Hot flashes are associated with increased pulse rate. Generally, they are a source of great physical and mental stress to the prostate cancer patient. The vasomotor hot flashes often warrant medical treatment, yet a satisfactory treatment having few side effects has not been forthcoming.
The patient experiences a hot flash as a suddenly occurring feeling of heat which spreads quickly from the face to the chest and back and then over the rest of the body. These attacks are usually accompanied by outbreaks of profuse sweating. These external signs of the activation of heat loss by the body arc associated with both dilatation of the cutaneous vessels and a decrease of the body temperature, which can be demonstrated as objective signs. Hot flash attacks are usually difficult to register because of their transient and unpredictable nature. However, in 13 castrated prostate cancer patients who reported hot flashes, Froedin et al. (The Prostate (1985) 7: 203-208), recorded a significant increase in cutaneous blood flow and in sweating by the use of a laser-Doppler flowmeter and an evaporimeter. The rate of evaporation increased synchronously with the increase in cutaneous blood flow. The intensity of the attacks as experienced by the patients corresponded closely to recorded measurements. Quella et al. (Urol. Nurs., 14(4): 155-158 (1994)) conducted a qualitative study to determine the level of severity of the hot flash. They found a noted consistency between what men considered as mild, moderate, severe, and very severe hot flashes. The authors proposed definitions of hot-flash severity, in accordance with their findings.
The symptoms of hot flashes have been rarely reported in prostate cancer patients treated with estrogens such as diethylstilbestrol (DES) or with cyproterone acetate (CPA) or megestrol acetate either alone or in combination with DES. There is no apparent difference in vasomotor hot flash response with respect to whether the primary therapy is surgical or chemical castration, or among patients receiving various formulations of different LH-RH agonists. Treatment with pure antiandrogens (such as flutamide) in addition to surgical castration or to LH-RH agonist treatment does not appear to significantly influence either the frequency or severity of hot flashes nor the response to treatment.
Estrogens such as DES may be effective to decrease hot flashes, but at the risk of gynecomastia and increased cardiovascular morbidity.
Megestrol acetate, a progestational hormone, has been shown to reduce hot flashes in men and women. A short term study reported by Loprinzi et al., (N. Engl. J. Med. (1994) 331: 347-352), indicated that low-dose megestrol acetate given to prostate patients who had undergone a surgical bilateral orchiectomy or treated with a gonadotropin-releasing-hormone agonist, reduced hot flashes by 50% in seventy-nine percent of the men in group 1 (those receiving megestrol acetate first) and in 12% of the men in group 2 (those receiving placebo first).
Megestrol acetate is indicated for the palliative treatment of advance breast and endometrium cancer and should not be used in lieu of surgery, radiation or chemotherapy. Weight gain associated with increased appetite is a frequent side effect of megestrol acetate. The drug is also indicated for the treatment of anorexia, cachexia, or a significant weight loss in patients diagnosed with AIDS. (Mosby's GenRx 1998, Megestrol Acetate.) Megestrol acetate has been shown to be effective therapy for metastatic prostate cancer. (Wehbe, et al., Mayo Clin. Proc. (October 1997) 72: 932-934, 932). Possible effects of low doses of megestrol acetate on the courses of hormonally sensitive tumors such as prostate tumors, are apparently unknown. See Loprinzi et al. (N. Engl. J. Med. (1994) 331: at 351).
Dawson et al. (J. Urol. (1995) 153: 1946-1947) show a paradoxical increase in prostate specific antigen (PSA) over time with megestrol acetate treatment as well as the marked increase in PSA after reinitiation of treatment with megestrol acetate in a patient with progressive metastatic prostate cancer. Dawson et al. also report a dramatic decrease in prostate specific antigen (PSA) after discontinuation of megestrol acetate. The case report concerned an orchiectomized prostatic cancer patient with metastatic disease who began megestrol acetate treatment during a period of tumor regression and stabilization. The condition remained stable for nearly two years. By that time, PSA reportedly increased from about 34 ng/ml to about 50 ng/ml, and then steadily increased over the next two months to about 110 ng/ml, when megestrol acetate was withdrawn. After PSA returned to about 40 ng/ml, reinitiation of megestrol acetate gradually caused an increase in PSA over the next three months to 149 ng/ml, at which time megestrol acetate was again discontinued. Wehbe et al. (Mayo Clin. Proc. (October 1997) 72: 932-934), reported a similar case. Stage IV metastatic prostate cancer was diagnosed in a patient with increased PSA levels. After initial treatment with leuprolide, the patient received megestrol acetate and continued hormone suppression with leuprolide. PSA levels reportedly decreased from 69 ng/ml to 31 ng/ml. By nine months after the start of treatment, however, PSA began a slow increasing trend, which later accelerated. By thirteen months after start of treatment, the PSA increased to 370 ng/ml (about a 12-fold increase), when megestrol acetate was discontinued. The PSA level then decreased over three months to 2 ng/ml, the substantial withdrawal decrease noted by the authors.
The Food and Drug Administration reported that evidence has been accumulating supporting the glucocorticoid activity of megestrol acetate in the patients who received it, most of whom were at an advanced stage of malignant disease. (Mann, et al., Arch. Intern. Med. (August 1997) 157: 1651-1656.) Cases of Cushing Syndrome were reported in women and diabetes mellitus and adrenal insufficiency associated with megestrol acetate were identified and reported in men and women. The exposure of patients with Cushing Syndrome to megestrol acetate was calculated to be 1440-20,000 mg.times.mo, whereas patients experiencing hyperglycemia generally had a lower exposure of 120-800 mg.times.mo. Patients with adrenal insufficiency had a wide range of exposure (from 90 to 32,000 mg.times.mo). Clinical complaints characteristic of adrenal suppression included nausca, vomiting, dizziness or hypertension, weight loss, or profound fatigue.
The use of megestrol acetate involves drawbacks in terms of an eventual dramatic increase in PSA for long-term use. It also appears that it should not be used intermittently, at least once PSA levels have notably increased and megestrol acetate has been withdrawn. Adverse effects associated with the glucocorticoid effects of the drug also may have a negative impact on quality of life of the patient.
It is generally thought that sudden reduction in the level of sex steroids precipitates hot flashes. The absence of hot flashes in aging men and the high frequency in postmenopausal women is believed to reflect the gradual change in male testicular function with age as compared with the abrupt reduction in female hormones at the menopause. The advanced age and hence reduced testosterone concentrations of men undergoing surgical or chemical castration for prostate cancer is thought to explain the absence of hot flashes in some patients after this treatment. In both sexes, hot flashes are usually associated with clinical situations which can most appropriately be defined as acquired gonadal insufficiency. This applies to the situation of prostate cancer patients after surgical castration and under LH-RH agonist therapy, as well as to women after the menopause. In all cases, the occurrence of hot flashes is preceded by a marked sudden decrease of previously normal levels of sex steroid.
Normal endocrine regulation in the hypothalamus involves a negative feedback mechanism in which the sex steroid levels influence LH-RH release, i.e., high sex steroid levels reduce LH-RH release and vice versa. These opposing influences are mediated via two intermediate components--inhibitory opioids and stimulatory catecholamines. When the sex steroid level is low, for example, a smaller amount of opioid-peptides is released, leading to an increase in the catecholamine concentration and, consequently, the increased release of LH-RH.
A possible characterization of the intrahypothalamic situation in patients suffering from hot flashes is that it is accompanied by a decrease of inhibitory opioids, an increase of catecholamines (adrenergic activity) and increased LH-RH release. Catecholamines such as norepinephrine are involved in the physiological regulation of body temperature. In view of the close anatomical relationship between the thermoregulatory center and the LH-RH neurons, an increase in the intrahypothalamic concentration of catecholamines stimulates not only the LH-RH secreting neurons, but also the neurons involved in thermoregulation, i.e., "the watering can effect". This stimulation leads to activation of heat loss, which manifests itself clinically as a hot flash. Vasomotor hot flashes and sweats can thus occur as a result of a disturbance of thermoregulation.
Opioids are indirectly involved in the genesis of hot flashes via the absence of their inhibitory effect on the release of catecholamines. In contrast, the increased release of LH-RH apparently plays no role in the induction of hot flashes as it occurs as a result of the increased concentration of catecholamines. The reduction of the testosterone level secondary to orchiectomy provokes a counter-regulatory effect with an intrahypothalamic increase of adrenergic activity, from which hot flashes result. The same applies to medical castration with LH-RH agonists. The occurrence of hot flashes is not prevented by additional administration of pure antiandrogens, since these substances have no inhibitory effect on the increased adrenergic activity in the hypothalamus.
Cyproterone acetate ("CPA") is disclosed in U.S. Pat. No. 3,234,093, which is incorporated herein by reference. CPA, a synthetic 21-carbon hydroxyprogesterone derivative, is a steroidal antiandrogenic agent that inhibits the action of adrenal and testicular androgens on prostatic cells, resulting in total androgen blockade. Additionally, due to the antigonadotropic effects of its progestogenic activity, CPA causes a centrally mediated reduction in testicular secretion of androgens. CPA is approved for use in many countries throughout Europe, Asia, Australia, South America and Canada. It is used as a component of oral contraceptives and in the treatment of acne, seborrhea, hirsutism, precocious puberty, hypersexuality and in the treatment of prostate cancer. The pharmaceutical preparations Androcur.RTM., Cyprostat.RTM., Diane.RTM., Dianette.RTM. are CPA-based products. Manufacturers of these products include Schering AG, Berlin, Germany and Berlex, Canada.
Since 1966, CPA has been used in combination with bilateral orchiectomy to achieve total androgen blockade in the treatment of prostate cancer. CPA has also been administered as monotherapy for prostate cancer. Dosages of 250-300 mg/day are used to bring about a complete anti-androgenic blockade. Dosages prescribed are usually 200-300 mg/day, divided into 2-3 doses. After orchiectomy a lower daily dose of 100-200 mg may be recommended. In a study reported in 1972 by Bracci and Di Silvero (discussed in Goldenberg, S. L. et al., Pharmanual 1994, Current Perspectives on the Expanding Role of Androcur,.RTM. Pharma Libri Publishers Inc., p. 23-24), CPA was administered at 100 mg/day or more with orchiectomy to patients with various advanced tumors for more than 2 years. The investigators noted that CPA in combination with orchiectomy has marked therapeutic effectiveness.
Side effects most frequently recorded with CPA treatment relate to the hormonal effects of the drug. These include impotence, inhibition of spermatogenesis and gynecomastia. These reactions are usually reversible upon discontinuation of therapy or reduction in dose. The drug is also associated with rapid falls in serum testosterone levels, which may also produce such central nervous system effects as fatigue, weakness, and headache.
Unlike other androgen deprivation therapies, CPA is rarely associated with hot flashes. Prostate cancer patients receiving CPA combined with surgical or chemical castration are less likely to experience hot flashes than those who do not receive CPA. (Barradell et al., Drugs & Aging (1994) 5/1:59-80.) CPA has a low incidence of side effects and its antigonadotropic and antiandrogenic effects are reversible, which enables intermittent therapy. CPA also has the added benefit of being "cancerocidal" to prostate cancer cells due to its potent antiandrogenic activity.
Another beneficial effect seen with CPA treatment has been the prevention of exacerbated bone pain. Patients with Stage C and D prostate cancer indicated improvement in bone pain with CPA as monotherapy. (Barradell et al., Drugs & Aging (1994) 5/1: 59-80). Overall, pain relief has been noted in 50-80% of patients receiving treatment with ANDROCUR.RTM.. (The Androcur Monograph, Berlex, Canada (1997)). The effect of CPA on pain generally paralleled its effect on metastasis. Id. When metastasis remained improved or stabilized, the analgesic requirement was also reduced. Id.
It has also been reported that exacerbated bone pain associated with the flare reaction at the start of LH-RH agonist treatment is prevented with CPA administered to prevent acute flare-up of prostatic disease. The Goldenberg, S. L. et al., Pharmanual cited above, indicates that Claes H., et al., in Murphy GP (Prostate Cancer, Part A: Research, Endocrine Treatment, and Histopathology, New York, N.Y.: Alan R. Liss (1987) 229-236), found that 58.5% of 17 patients who received goserelin alone experienced a transient increase in bone pain compared with none of 7 patients who received goserelin acetate plus 200 mg/day CPA. For the short-term prevention of tumor flare, CPA has been administered with an LH-RH agonist generally at 150 to 300 mg/day dosages. Also for tumor flare, CPA has been administered at 100 mg/day in combination with 0.1 mg/day DES. (Bruchovsky et al., Cancer 71: 7282-2790 (1993)).
The Androcur.RTM. Monograph, Berlex Inc., Canada (1997), indicates a general improvement in the subjective assessment of the quality of life in 70% of 367 evaluable patients participating in worldwide studies on CPA, based on criteria of general improvement in quality of life. The criteria listed are weight gain and pain relief. The patients considered included ones who received CPA as monotherapy, an estrogen refractory group, and orchiectomized patients. It appears that dosage forms included oral and i.m. injection and that the doses varied. Most patients who received oral CPA were dosed at 200 to 300 mg/day. The lowest oral dose possibly given to orchiectomized patients was indicated to be 100 mg/day. The data provided indicate the percent of patients in each of the three patient groups with complete or partial remissions. For previously untreated patients, Androcur.RTM. treatment resulted in 50% remission; for estrogen refractory patients, Androcur.RTM. treatment resulted in 44% remission; for orchiectomized patients, Androcure patients had a 60% remission. There is no indication of percent improvement subjectively assessed by group or by dosage administered.
Dose-related hepatic toxicity in humans has been reported with the prolonged use of CPA. Toxicological studies have revealed, however, that administration of CPA to humans does not pose a serious risk of hepatotoxicity. A retrospective liver toxicity analysis was performed on 89 patients with advanced prostatic cancer who underwent orchiectomy and who received continuous additional antiandrogenic treatment with 50 mg/day CPA. (Hinkel et al., Eur. Urol. (1996) 30:464-470). CPA was administered to these patients for a period spanning from 2 to 152 months starting at the time of diagnosis. Various medications were frequently prescribed besides CPA treatment. Although a proper control group was lacking, in no case was CPA discontinued due to its side effects. After evaluating the patients' liver function, the authors concluded that CPA is a reliable drug to inhibit androgen synthesis with maximum efficacy and safety in the treatment of prostate cancer.
Moreover, a thorough review on the toxicology of CPA was published by Rabe et al. (Drug Safety (1996 (Jan.)); 14(1):25-38). In a multi-center surveillance study of long term CPA use in over 2500 patients, the treatment group included men and women. The men were treated at dosages of either more than 200 mg/day or from 100 to 200 mg/day CPA. No correlation was found between the duration of CPA treatment and the prevalence of liver enzyme elevations. Not a single case of hepatocellular carcinoma was observed. The authors concluded that there were no observations that would indicate an increased risk of proliferative liver change as a result of CPA treatment.
The minimum dosage of CPA for an antigonadotropic effect in men may not be precisely known. The threshold value for an antiandrogen effect in men was indicated to be 50 mg according to U.S. Pat. No. 3,895,110, which issued in 1975. Presumably then, the threshold value for an anticancerocidal dosage in prostate cancer patients may also be 50 mg. Blood levels of CPA are known to be generally dose dependent.
In a double-blind, crossover trial, Eaton and McGuire treated 12 prostate cancer patients with troublesome post-orchiectomy hot flashes with CPA or placebo. (Eaton AC, McGuire N., Lancet (1983) 8363: 1336-1337). They reported that the frequency of hot flashes was significantly reduced during the three weeks that CPA (100 mg three times daily) was given. The 1994 Barradell et al. review article cited above summarizes the Eaton et al. data as reducing hot flashes from a mean number of 9.44 per day before CPA treatment to 2.26 per day after the 21 day treatment period. Five patients complained of lassitude while on this regimen. In one patient the lassitude was reportedly severe. The dosage of CPA was reduced to 100 mg/day for this patient and it was stated to completely suppress vasomotor symptoms without side effects. The article provides no indication of a "wash-out" period between dosages or of how long this single patient was administered 100 mg CPA daily before this observation was made.
Bruchovsky et al. (Cancer 71: 2782-2790 (1993)), report administration of 100 mg/day CPA in combination with 0.1 mg/day DES to eliminate the flare reaction encountered upon the first administration of LH-RH agonist. CPA treatment was then maintained to reportedly suppress vasomotor symptoms, citing the Eaton paper. The dosage administered was increased in some patients.
Moon reported anecdotal evidence of the efficacy of CPA in the treatment of hot flashes. (Moon T D, Letter to the Editor. J. Urol. (1985) 134: 155-156). A patient who underwent orchiectomy for metastatic carcinoma of the prostate had been troubled with 10 to 15 hot flashes daily. These episodes lasted only a few minutes but they were bothersome and accompanied by marked facial sweating. Treatment with estrogens was contraindicated because of angina and a previous myocardial infraction. This patient was treated initially with 100 mg CPA three times a day and a good response was obtained. The drug was then discontinued and the hot flashes increased during the next few weeks and were back to pre-treatment numbers by four weeks. CPA was then administered at 50 mg two times per day. Moon stated that there was a significant reduction in the number of hot flashes and that the severity of the remaining hot flashes was much reduced in this patient.
Noting the importance of a large scale randomized clinical trial in view of a considerable placebo effect reported in the treatment of hot flashes in menopausal women, Kramer et al., cited above, reported in 1992 a trial of 273 patients treated with CPA who had previously undergone orchiectomy and who had the mere occurrence of hot flashes and/or outbreaks of sweat. The investigators chose 150 mg/day CPA (50 mg t.i.d.) as their treatment dose. After six months of treatment with CPA the number of patients experiencing hot flashes or outbreaks of sweating decreased as compared with placebo. Hot flashes were reportedly experienced by 33% of patients receiving CPA and 61% of patients receiving placebo, while 24% of CPA-treated patients had outbreaks of sweating compared with 47% of placebo-treated patients. Although no data were provided, in those patients receiving CPA who continued to experience hot flashes or sweating, the frequency and severity were stated to be strongly reduced.
In several randomized well-controlled clinical trials in prostate cancer patients, if CPA was given in combination with LH-RH agonists such as Zoladex.RTM., or Buserlin.RTM., there was a reduction in the percentage of patients reporting hot flashes. (De Voogt et al., J. Steroid Biochem. Nolec. Biol. (1990) 37: 965-969; DiSilverio, et al., Eur. Urol. (1990) 18 (suppl 3): 54-61; Thorpe et al., Eur. Urol. (1996) 29/1:47-54.) A 1994 review article by Barradell L B, et al. (Drugs & Aging (1994) 5/1: 59-80), summarized that while no studies have been done objectively assessing quality of life per se, the effect of CPA used at dosages of 150 to 300 mg/day on the incidence of hot flushes has been favorable for patients undergoing pharmacological or surgical castration.
U.S. Pat. No. 3,895,110 to Itil et al. (which issued in 1975) disclosed the treatment of psychic disturbances of the affective or behavioral type within a broad potential dosage range of CPA. The Itil patent recommends, however, treating at a dosage of CPA under the threshold value for an antiandrogen effect in both men and women. The Itil patent reports significant remission of premenstrual anxiety and tension conditions in women. A study on five males suffering from symptoms of anxiety characterized by nervousness, restlessness, anxiety, headache, and tachycardia, treated with 1 to 6 mg CPA daily for 2 weeks, was also reported. The Itil patent indicates that the results in the men were mixed. Moreover, in one patient showing moderate improvement at 3 to 4 mg per day, an increased dosage resulted in restlessness in the patient.
Goldenberg et al. (J. Urol. (1988) 140: 1460-1465) reported that CPA and low dose DES may be co-administered to achieve a synergistic androgen withdrawal effect in the treatment of advanced prostatic carcinoma. CPA administered at 200 mg/day with 0.1 mg daily DES showed a marked decrease in serum testosterone, with no change upon decreasing CPA to 100 mg/day in the combination. In a subsequent report, Goldenberg et al. (Urology 47 (6) (1996) 882-884) indicate that 100 mg CPA and 0.1 mg DES per day result in persistent decrease in serum testosterone with a lower incidence of side effects than the 200 mg/day CPA combination. Bruchovsky et al. (Cancer 71: 2782-2790 (1993)) report elimination of flare reaction by pretreatment with CPA and low-dose DES. Patients were pretreated with 100 mg per day CPA and 0.1 mg/day DES for 4 weeks. Goserelin acetate was then given and CPA/DES was continued. DES administration was discontinued at 8 weeks to eliminate associated minor toxicity. Both Goldenberg et al. articles report that during the administration of CPA and DES in combination, hot flashes/night sweats were incident in 8% of patients.
Goldenberg et al. (J. Urol. (1988) 140: 1460-1465) indicate that the weakening of the antigonadotropic effect of CPA, seen after 6 to 9 months, was not observed with the continued co-administration of DES.
It has also been forwarded that estrogens may increase prostatic cancer growth. In the treatment of prostate cancer, U.S. Pat. No. 5,610,150 discloses a combination therapy for prostate cancer treatment that includes an antiantrogen, a sex steroid biosynthesis inhibitor and an antiestrogen for the prevention of the biosynthesis of estrogen.
Estrogens have been shown to be effective in the treatment of hot flashes. Conjugated estrogens such as Premarin.RTM. are indicated for the treatment of vasomotor hot flashes in menopausal women.
Estrogens also have a testosterone-reducing effect that is based to a large extent on the increased release of inhibitory factors from the hypothalamus in addition to a direct effect on the pituitary gland. As a result, it is thought that the occurrence of intrahypothalamic counter-regulation of catecholamines (adrenergic activity) is impeded and the disturbance of thermoregulation prevented.
Miller et al. (Urology (1992) 40: 499-502) report treating 12 prostate cancer patients suffering from severe symptoms of post-orchiectomy hot flashes and sweats with 0.33 mg DES daily. Nine patents demonstrated both objective and subjective improvement in symptoms. Five patents experienced adverse drug reaction including onset of gynecomastia. Atala et al. (Urology (1992) 19: 108-110) report that of bilateral orchiectomy patients reporting vasomotor symptoms, the frequency and severity of hot flashes were significantly reduced during the time 1 mg/day DES was given.
Chlorotrianisene, an estrogen which was sold in the United States under the name TACE.RTM., was indicated for the palliative therapy of advanced prostatic carcinoma and for moderate to severe vasomotor symptoms associated with the menopause, among other things. For long-term treatment of progressive prostatic cancer, 12 mg to 25 mg daily was prescribed. For cyclic short term use in women to treat severe vasomotor symptoms, the same dosage amount was usually prescribed. (Physicians' Desk Reference, 35th Edition (1981).
There remains no suitable treatment for vasomotor hot flush in surgically or chemically castrated prostatic cancer patients. A method for treating hot flashes and sweats that accompany androgen ablation therapy of prostate cancer has long been desired and will fulfill an important medical need.